National PBM Drug Monograph Epinastine (Elestat™) May 2004 VHA Pharmacy Benefits Management Strategic Healthcare Group and the Medical Advisory Panel EXECUTIVE SUMMARY • Antihistamine ophthalmic drops provide quick relief from allergic conjunctivitis (AC) symptoms such as itching and redness, without the potential adverse effects associated with systemic absorption. • Epinastine is the fourth ophthalmic antihistamines/mast cell stabilizer approved for the itching associated with AC. Other ophthalmic preparations for allergic conjunctivitis include antihistamines, mast cell stabilizers, nonsteroidal anti-inflammatory agents (NSAIDs), corticosteroids, decongestants, and decongestant/antihistamines. • An ideal agent would offer improved efficacy and safety, reduce polypharmacy as a combination product or through replacing oral agents, and provide evidence for chronic AC prevention. INTRODUCTION1 The purposes of this monograph are to (1) evaluate the available evidence of safety, tolerability, efficacy, cost, and other pharmaceutical issues that would be relevant to evaluating epinastine ophthalmic solution for possible addition to the VA National Formulary (VANF); (2) define its role in therapy; and (3) identify parameters for its rational use in the VA. PHARMACOLOGY/PHARMACOKINETICS1, 2 Antihistamines are receptor antagonists used to avoid the inflammatory effects of histamine. Taken orally, these agents have been shown to be effective for treating allergic symptoms such as pruritis (itching). Epinastine in particular has been found to have a rapid onset of action.3 Topical antihistamine eye drops provide relief from ocular symptoms without systemic absorption or related adverse events, allowing for the combination of oral and topical agents when indicated. Ophthalmic antihistamine/mast cell stabilizers such as epinastine combine H1-receptor actions to block ocular itching and redness with H2-receptor affinity. The H2-receptor activity limits vasodilatation, stabilization of mast cell and basophil surfaces, vascular permeability, and mucous discharge which all contribute to the inflammatory response of further redness. Additionally, epinastine has affinity for the α1-, α2-, and 5-HT2-receptors, however ocular effects on glaucoma or serotonin-related congestion have not been studied.4,5 Epinastine ophthalmic solution does not penetrate the blood/brain barrier. May 2004 Updates may be found at http://vaww.pbm.med.va.gov or www.vapbm.org National PBM Drug Monograph - Epinastine (Elestat™) Azelastine 0.05% Epinastine 0.05% (Elestat, Ketotifen 0.025%, Olopatadine 0.1% (Optivar, MedPointe)6 Allergan/Inspire) (Zaditor, CIBA (Patanol, Alcon)8 Vision)7 Onset n/a Rapid, 3-5 minutes n/a n/a Duration n/a 8 hours n/a >8 hours Metabolism cP450 < 10% n/a Minimal Elimination Clearance 0.5L/hr/kg; Total clearance 56 L/hr; IV n/a 60-70% unchanged renal 75% in feces, 10% dose excreted unchanged renal unchanged (55%) via active tubular secretion; 30% fecal elimination Half-life 22 hours Plasma 12 hours n/a Plasma 3 hours Protein 88%, metabolite 97% 64% n/a n/a Binding/ bound h=hour; IV=intravenous; kg=kilogram; L=liter min.=minutes; n/a= not available ADVERSE EVENTS2 Ocular adverse events occurred in 1-10% of patients studied, including burning sensation in the eye, folliculosis (inflammation of the eyelid causing pain, swelling or irritation), hyperemia (redness), and pruritis. Non-ocular events included cold symptoms and upper respiratory infections in approximately 10% of patients, and headache, rhinitis, sinusitis, increased cough, and pharyngitis reported in 1-3%. Most of the adverse effects reported are expected in the allergic patient. Warnings Contraindicated if hypersensitivity to epinastine or any of the vehicle’s components. Elestat™ ophthalmic solution is for topical use only. Precautions Contact lenses should not be worn if eye is red and epinastine should not be used for contact lens irritation. Prior to epinastine use, contact lenses should be removed; patients should wait 10 minutes before reinserting due to the risk of the benzalkonium chloride preservative absorbing into the lenses. Epinastine is pregnancy category C; animal models have shown conflicting outcomes and should only be used in pregnant or nursing mothers if the potential benefit outweighs the risk. Special Populations There is insufficient published data on pediatric patients under the age of 3 years. Geriatric patients >65 years of age have been included in clinical trials with no differences in safety or efficacy compared to the other subjects. Co-morbidities, race, and concomitant medications have not been studied. May 2004 2 Updates may be found at http://vaww.pbm.med.va.gov or www.vapbm.org National PBM Drug Monograph - Epinastine (Elestat™) CLINICAL TRIALS Citation Whitcup S, Bradford R, Lue J, et al. Efficacy and tolerability of ophthalmic epinastine: A randomized, double-masked, parallel-group, active-and-vehicle-controlled environmental trial in patients with seasonal allergic conjunctivitis. Clin Ther. 2004; 26(1):29-34. Study To assess the efficacy and tolerability of epinastine ophthalmic solution in patients with seasonal Goals allergic conjunctivitis (SAC). Methods Study Design: Multicenter, double masked, parallel-group, active- and vehicle-controlled, environmental trial. Patients were randomized (block stratified by age) in a 2:2:1 ratio to 1 drop/eye bid (morning and afternoon) of epinastine 0.05% solution, levocabastine 0.05% suspension, or vehicle of epinastine for 8 weeks. Bottles were masked for blinding. Washouts: 14-days for steroids and mast cell stabilizers; 7 days for fexofenadine, loratadine and cetirizine; 3-days for ASA, H1 –receptor antagonist antihistamines or any other topical ophthalmics. Primary analysis was average worst daily ocular itching (scale of 0-4), based on two 1-week periods with the highest pollen counts and assessed tid as mean of worst all-day and bedtime scores. Secondary end points included ocular hyperemia (redness) with a scale of 0-4 and photos, chemosis, ocular mucous discharge (scale 0-4); eyelid swelling (scale 0-3) and tearing (present or absent). Baseline: 298 patients, 53.4% female, 46.3% Asian, mean age 32.7 (range 9-71 years), prestudy NS differences in population. Conducted March 20, 2001 - July 17, 200 in West, Midwest, South and East Coast centers. Lowest mean pollen counts 8.2 grains/m3, highest 97.5 grains/m3. Data Analysis: Performed in intent-to-treat (ITT) population. Wilcoxon rank-sum test instead of ANOVA for between group diaries due to skewed distribution. Noninferior defined as UL of 2-sided 95% CI of epinastine minus levocabastine group <0.4. Null hypothesis of no difference between groups at p≤0.05. Slit-lamp and AEs (mild, moderate or severe) by Pearson chi-square or Fisher exact test (if 25% of cell counts were <5); visual acuity data by Fisher exact test. Criteria Inclusions: ≥9 years of age, history of SAC or rhinoconjunctivitis; allergen sensitivity=positive grass skin-prick test within 2 years prior and bilateral ocular response to low dose grass pollen with the conjunctival allergen challenge (CAC); best-corrected visual acuity using Early Treatment Diabetic Retinopathy Study (ETDRS) chart, calculated logarithm of the minimal angle of resolution (logMAR) ∃0.7 and avoided contact lenses 15 minutes after administration and study visits. Exclusions: Pregnant or nursing, ocular infection or condition such as blepharitis, follicular conjunctivitis, iritis, diagnosis of dry eye, retinal detachment or disease, history of asthma to study antigens, systemic autoimmune disease. Results Primary end point: Ocular itching p=0.045 epinastine vs. vehicle, UL 95% CI median shift of epinastine and levocabastine was <0.4, 0.00 (-0.20 to 0.10) therefore epinastine was noninferior. Secondary end points: Ocular hyperemia was NS versus vehicle and noninferior to levocabastine (median shift, 95% CI= -0.10 (-0.30 to 0.10). Chemosis, ocular mucous discharge, eyelid swelling and tearing NS. Tolerability: AEs reported in 1.7 - 3.6% of patients, most common reaction was stinging in <1.6% of patients. Slit-lamp biomicroscopy, visual acuity, other AEs NS; 3 patients withdrew due to AEs. Conclusion Marginally statistically significant difference between epinastine and vehicle for worst ocular itching. Noninferior to levocabastine for ocular itching. Critique Strengths: Multi-center across all regions, environmental study is realistic clinical setting, efficacy and tolerability by ITT. Limitations: The pollen counts were low, wide-ranging, and varied among sites. Worst ocular itching (SD) was very low on scale 0-4: epinastine 0.77 (0.86), levocabastine 0.86 (0.86), and vehicle 0.93(0.76). Sponsored by the manufacturer. May 2004 3 Updates may be found at http://vaww.pbm.med.va.gov or www.vapbm.org National PBM Drug Monograph - Epinastine (Elestat™) Citation Abelson M, Gomes P, Crampton H, et al. Efficacy and tolerability of ophthalmic epinastine assessed using the conjunctival antigen challenge model in patients with a history of allergic conjunctivitis. Clin Ther. 2004; 26(1):35-47. Study To assess the efficacy and tolerability of epinastine ophthalmic solution in patients with allergic Goals conjunctivitis using the conjunctival antigen challenge (CAC) model. Methods Study Design: Single-center, double masked, parallel-group, vehicle-controlled trial. Randomized (computer-generated) by eye to a single dose of 1 drop of epinastine 0.05% solution and 1 drop of vehicle of epinastine in the other eye 15 minutes